This invention relates to methods and kits for treating osteoarthritis using an estrogen agonist/antagonist.
Osteoarthritis is the most common joint disorder and is characterized by loss of joint cartilage and hypertrophy of bone at the joint. This disorder usually begins asymtomatically in the 2nd to 3rd decade of life and is very common by age seventy. Almost all persons by age forty have some pathological change in weight-bearing joints. Men and women are equally affected, but onset is earlier in men.
Joint cartilage, also called hyaline cartilage, is made up of 95% water and extracellular matrix and 5% chondrocytes. The extracellular matrix comprises proteoglycans and Type II collagen.
Osteoarthritis is a progressive disease. Typical symptomatic treatment includes the management of pain that accompanies osteoarthritis and changes in lifestyle such as diet and exercise. Examples of compounds that have been used to treat the pain associated with osteoarthritis include acetominophen and nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen, ketoprofen, nabumetone, etodolac, salsalate, sulindac, diclofenac, tolmetin, flurbiprofen, piroxicam, fenoprofen, indomethacin, meclofenamate, oxaprozin, diflunisal, and ketorolac; and selective cyclooxygenase-2 (COX-2) inhibitors such as Celebrex(copyright) and Vioxx(copyright). Because NSAIDs can have unwanted side effects such as ulcers, NSAIDs are sometimes administered with other compounds that ameliorate the side effects of the NSAIDs. Typical compounds that are used in combination with NSAIDs include proton pump inhibitors such as omeprazole; antacids such as sucralfate; and H2 blockers such as ranitidine, cimetidine, famotidine, and nizatidine. In addition, products derived from natural substances have been used to treat osteoarthritis. Examples of natural substances include hyaluronic acid, glucosamine, chondroitin sulfate, and capsaicin. Intraarticular corticosteriods have also been used to treat osteoarthritis. Presently, there are no widely accepted treatments that reduce the progression of cartilage damage in osteoarthritis.
It has been found that chondrocytes, which are a main component of cartilage and produce proteoglycans and Type II collagen, contain estrogen receptors. The present invention provides methods for preventing or reducing the rate of cartilage degradation using an estrogen receptor agonist/antagonist.
The present invention provides methods of treating osteoarthritis, the methods comprising administering to a patient having or at risk of having osteoarthritis, a therapeutically effective amount of an estrogen agonist/antagonist of formula (I): 
wherein:
A is selected from CH2 and NR;
B, D and E are independently selected from CH and N;
Y is
(a) phenyl, optionally substituted with 1-3 substituents independently selected from R4;
(b) naphthyl, optionally substituted with 1-3 substituents independently selected from R4;
(c) C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R4;
(d) C3-C8 cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R4;
(e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94 and xe2x80x94S(O)nxe2x80x94, optionally substituted with 1-3 substituents independently selected from R4;
(f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94 and xe2x80x94S(O)nxe2x80x94 optionally substituted with 1-3 substituents independently selected from R4; or
(g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94 and xe2x80x94S(O)nxe2x80x94, optionally substituted with 1-3 substituents independently selected from R4;
Z1 is
(a) xe2x80x94(CH2)pW(CH2)qxe2x80x94;
(b) xe2x80x94O(CH2)pCR5R6xe2x80x94;
(c) xe2x80x94O(CH2)pW(CH2)qxe2x80x94;
(d) xe2x80x94OCHR2CHR3xe2x80x94; or
(e) xe2x80x94SCHR2CHR3xe2x80x94;
G is
(a) xe2x80x94NR7R8;
(b) 
wherein n is 0, 1 or 2; m is 1, 2 or 3; Z2 is xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH2xe2x80x94; optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R4; or
(c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R4; or
Z1 and G in combination may be 
W is
(a) xe2x80x94CH2xe2x80x94;
(b) xe2x80x94CHxe2x95x90CHxe2x80x94;
(c) xe2x80x94Oxe2x80x94;
(d) xe2x80x94NR2xe2x80x94;
(e) xe2x80x94S(O)nxe2x80x94;
(f) 
(g) xe2x80x94CR2(OH)xe2x80x94;
(h) xe2x80x94CONR2xe2x80x94;
(i) xe2x80x94NR2COxe2x80x94;
(j) 
(k) xe2x80x94Cxe2x89xa1Cxe2x80x94;
R is hydrogen or C1-C6 alkyl;
R2 and R3 are independently
(a) hydrogen; or
(b) C1-C4 alkyl;
R4 is
(a) hydrogen;
(b) halogen;
(c) C1-C6 alkyl;
(d) C1-C4 alkoxy;
(e) C1-C4 acyloxy;
(f) C1-C4 alkylthio;
(g) C1-C4 alkylsulfinyl;
(h) C1-C4 alkylsulfonyl;
(i) hydroxy (C1-C4)alkyl;
(j) aryl (C1-C4)alkyl;
(k) xe2x80x94CO2H;
(i) xe2x80x94CN;
(m) xe2x80x94CONHOR;
(n) xe2x80x94SO2NHR;
(o) xe2x80x94NH2;
(p) C1-C4 alkylamino;
(q) C1-C4 dialkylamino;
(r) xe2x80x94NHSO2R;
(s) xe2x80x94NO2;
(t) -aryl; or
(u) xe2x80x94OH;
R5 and R6 are independently C1-C8 alkyl or together form a C3-C10 carbocyclic ring;
R7 and R8 are independently
(a) phenyl;
(b) a C3-C10 carbocyclic ring, saturated or unsaturated;
(c) a C3-C10 heterocyclic ring containing up to two heteroatoms, selected from xe2x80x94Oxe2x80x94, xe2x80x94Nxe2x80x94 and xe2x80x94Sxe2x80x94;
(d) H;
(e) C1-C6 alkyl; or
(f) form a 3 to 8 membered nitrogen containing ring with R5 or R6;
R7 and R8 in either linear or ring form may optionally be substituted with up to three substituents independently selected from C1-C6 alkyl, halogen, alkoxy, hydroxy and carboxy;
a ring formed by R7 and R8 may be optionally fused to a phenyl ring;
e is 0, 1 or 2;
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
In a preferred embodiment of the methods, the estrogen agonist/antagonist is a compound of formula (IA) 
wherein G is 
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
In a preferred embodiment of the methods, the estrogen agonist/antagonist is (xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is in the form of a D-tartrate salt.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, droloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, EM-652, EM-800, GW 5638, GW 7604, and optical or geometric isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof. In addition, raloxifene can be used to prevent or reduce the rate of cartilage degradation.
Also provided are methods of treating osteoarthritis, the methods comprising administering to a patient having or at risk of having osteoarthritis, a therapeutically effective amount of an estrogen agonist/antagonist of formula V or VI: 
wherein:
R1B is selected from H, OH, xe2x80x94Oxe2x80x94C(O)xe2x80x94C1-C12 alkyl (straight chain or branched), xe2x80x94Oxe2x80x94C1-C12 alkyl (straight chain or branched or cyclic), or halogens or C1-C4 halogenated ethers;
R2B, R3B, R4B, R5B, and R6B are independently selected from H, OH, xe2x80x94Oxe2x80x94C(O)xe2x80x94C1-C12 (straight chain or branched), xe2x80x94Oxe2x80x94C1-C12 (straight chain or branched or cyclic), halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl (straight chain or branched), or trifluoromethyl;
XA is selected from H, C1-C6 alkyl, cyano, nitro, trifluoromethyl, and halogen;
s is 2 or 3;
YA is the moiety: 
wherein:
a) R7B and R8B are independently selected from the group of H, C1-C6 alkyl, or phenyl optionally substituted by CN, C1-C6 alkyl (straight chain or branched), C1-C6 alkoxy (straight chain or branched), halogen, xe2x80x94OH, xe2x80x94CF3, or xe2x80x94OCF3; or
b) R7B and R8B are concatenated to form a five-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1xe2x80x94C4)alkyl; or
c) R7B and R8B are concatenated to form a six-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
d) R7B and R3B are concatenated to form a seven-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
e) R7B and R8B are concatenated to form an eight-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
f) R7B and R8B are concatenated to form a saturated bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl;
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
In a preferred embodiment of the methods, the estrogen agonist/antagonist is the compound TSE-424 of formula Va below: 
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
Also provided are methods of treating osteoarthritis, the methods comprising administering to a patient having or at risk of having osteoarthritis, a therapeutically effective amount of an estrogen agonist/antagonist of formula IlIl (EM-652) below or formula IV (EM-800) below: 
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
The present invention provides kits for use by a consumer to treat osteoarthritis, the kits comprising:
(a) a pharmaceutical composition comprising an estrogen agonist/antagonist of formula (I): 
wherein:
A is selected from CH2 and NR;
B, D and E are independently selected from CH and N;
Y is
(a) phenyl, optionally substituted with 1-3 substituents independently selected from R4;
(b) naphthyl, optionally substituted with 1-3 substituents independently selected from R4;
(c) C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R4;
(d) C3-C8 cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R4;
(e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94 and xe2x80x94S(O)nxe2x80x94, optionally substituted with 1-3 substituents independently selected from R4;
(f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94 and xe2x80x94S(O)nxe2x80x94 optionally substituted with 1-3 substituents independently selected from R4; or
(g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94 and xe2x80x94S(O)nxe2x80x94, optionally substituted with 1-3 substituents independently selected from R4;
Z1 is
(a) xe2x80x94(CH2)pW(CH2)qxe2x80x94;
(b) xe2x80x94O(CH2)pCR5R6xe2x80x94;
(c) xe2x80x94O(CH2)pW(CH2)qxe2x80x94;
(d) xe2x80x94OCHR2CHR3; or
(e) xe2x80x94SCHR2CHR3xe2x80x94;
G is
(a) xe2x80x94NR7R8;
(b) 
wherein n is 0, 1 or 2; m is 1, 2 or 3; Z2 is xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH2xe2x80x94; optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R4; or
(c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R4; or
Z1 and G in combination may be 
W is
(a) xe2x80x94CH2xe2x80x94;
(b) xe2x80x94CHxe2x95x90CHxe2x80x94;
(c) xe2x80x94Oxe2x80x94;
(d) xe2x80x94NR2xe2x80x94;
(e) xe2x80x94S(O)nxe2x80x94;
(f) 
(g) xe2x80x94CR2(OH)xe2x80x94;
(h) xe2x80x94CONR2xe2x80x94;
(i) xe2x80x94NR2COxe2x80x94;
(j) 
(k) xe2x80x94Cxe2x89xa1Cxe2x80x94;
R is hydrogen or C1-C6 alkyl;
R2 and R3 are independently
(a) hydrogen; or
(b) C1-C4 alkyl;
R4 is
(a) hydrogen;
(b) halogen;
(c) C1-C6 alkyl;
(d) C1-C4 alkoxy;
(e) C1-C4 acyloxy;
(f) C1-C4 alkylthio;
(g) C1-C4 alkylsulfinyl;
(h) C1-C4 alkylsulfonyl;
(i) hydroxy (C1-C4)alkyl;
(j) aryl (C1-C4)alkyl;
(k) xe2x80x94CO2H;
(l) xe2x80x94CN;
(m) xe2x80x94CONHOR;
(n) xe2x80x94SO2NHR;
(o) xe2x80x94NH2;
(p) C1-C4 alkylamino;
(q) C1-C4 dialkylamino;
(r) xe2x80x94NHSO2R;
(s) xe2x80x94NO2;
(t) -aryl; or
(u) xe2x80x94OH;
R5 and R6 are independently C1-C8 alkyl or together form a C3-C10 carbocyclic ring;
R7 and R8 are independently
(a) phenyl;
(b) a C3-C10 carbocyclic ring, saturated or unsaturated;
(c) a C3-C10 heterocyclic ring containing up to two heteroatoms, selected from xe2x80x94Oxe2x80x94, xe2x80x94Nxe2x80x94 and xe2x80x94Sxe2x80x94;
(d) H;
(e) C1-C6 alkyl; or
(f) form a 3 to 8 membered nitrogen containing ring with R5 or R6;
R7 and R8 in either linear or ring form may optionally be substituted with up to three substituents independently selected from C1-C6 alkyl, halogen, alkoxy, hydroxy and carboxy;
a ring formed by R7 and R8 may be optionally fused to a phenyl ring;
e is 0, 1 or 2;
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof, and a pharmaceutically acceptable carrier, vehicle or diluent; and
(b) instructions describing a method of using the pharmaceutical composition to treat osteoarthritis.
In a preferred embodiment of the kits, the estrogen agonist/antagonist is a compound of formula (IA): 
wherein G is 
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
In another preferred embodiment of the kits, the estrogen agonist/antagonist is (xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
In another preferred embodiment of the kits, the (xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol is in the form of a D-tartrate salt.
In another preferred embodiment of the kits, the estrogen agonist/antagonist is selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, droloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, EM-652, EM-800, GW 5638, GW 7604 and optical or geometric isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.
Also provided are kits for use by a consumer to treat osteoarthritis, the kits comprising:
(a) a pharmaceutical composition comprising an estrogen agonist/antagonist of formula V or VI: 
wherein:
R1B is selected from H, OH, xe2x80x94Oxe2x80x94C(O)xe2x80x94C1-C12 alkyl (straight chain or branched), xe2x80x94Oxe2x80x94C1-C12 alkyl (straight chain or branched or cyclic), or halogens or C1-C4 halogenated ethers;
R2B, R3B, R4B, R5B, and R6B are independently selected from H, OH, xe2x80x94Oxe2x80x94C(O)xe2x80x94C1-C12 (straight chain or branched), xe2x80x94Oxe2x80x94C1-C12 (straight chain or branched or cyclic), halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl (straight chain or branched), or trifluoromethyl;
XA is selected from H, C1-C6 alkyl, cyano, nitro, trifluoromethyl, and halogen;
s is 2 or 3;
YA is the moiety: 
wherein:
a) R7B and R8B are independently selected from the group of H, C1-C6 alkyl, or phenyl optionally substituted by CN, C1-C6 alkyl (straight chain or branched), C1-C6 alkoxy (straight chain or branched), halogen, xe2x80x94OH, xe2x80x94CF3, or xe2x80x94OCF3; or
b) R7B and R8B are concatenated to form a five-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
c) R7B and R8B are concatenated to form a six-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
d) R7B and R8B are concatenated to form a seven-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
e) R7B and R8B are concatenated to form an eight-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
f) R7B and R8B are concatenated to form a saturated bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof, and a pharmaceutically acceptable carrier, vehicle or diluent; and
(b) instructions describing a method of using the pharmaceutical composition to treat osteoarthritis.
Also provided are kits for use by a consumer to treat osteoarthritis, the kits comprising:
(a) a pharmaceutical composition comprising an estrogen agonist/antagonist of formula Va (TSE-424) below: 
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof, and a pharmaceutically acceptable carrier, vehicle or diluent; and
(b) instructions describing a method of using the pharmaceutical composition to treat osteoarthritis.
Also provided are kits for use by a consumer to treat osteoarthritis, the kits comprising:
(a) a pharmaceutical composition comprising an estrogen agonist antagonist of formula III (EM-652) below or formula IV (EM-800) below: 
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof, and a pharmaceutically acceptable carrier, vehicle or diluent; and
(b) instructions describing a method of using the pharmaceutical composition to treat osteoarthritis.
In a preferred embodiment of the kits, the kits further comprise an additional compound that is useful to treat osteoarthritis arthritis.
In a preferred embodiment of the kits with an additional compound, the additional compound is a nonsteroidal anti-inflammatory drug.
In a preferred embodiment of the kits with an additional compound, the additional compound is a COX-2 inhibitor.
In a preferred embodiment of the kits with an additional compound, the additional compound is a COX-2 inhibitor and the COX-2 inhibitor is Celebrex(copyright) or Vioxx(copyright).
Also provided are kits for use by a consumer to treat osteoarthritis, the kits comprising:
(a) an estrogen agonist/antagonist;
(b) a COX-2 inhibitor;
(c) instructions describing a method of using the estrogen agonist/antagonist and COX-2 inhibitors to treat osteoarthritis; and
(d) a container for the estrogen agonist/antagonist, COX-2 inhibitor, and instructions.
In a preferred embodiment of the kits, the estrogen agonist/antagonist is (xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof, and the COX-2 inhibitor is Celebrex(copyright) or Vioxx(copyright).
Also provided are methods of treating osteoarthritis, the method comprising the step of administering to a patient having or at risk of having osteoarthritis, an estrogen agonist/antagonist and a COX-2 inhibitor.
In a preferred embodiment of the methods, the estrogen agonist/antagonist is (xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof, and the COX-2 inhibitor is Celebrex(copyright) or Vioxx(copyright).